Droxidopa is a known synthetic amino acid precursor of norepinephrine that is converted directly to norepinephrine via the action of dopa decarboxylase (DDC). Droxidopa is generally used to treat orthostatic hypotension (OH) and can be categorized as an antiparkinsonian agent; however, multiple pharmacological activities have been observed with droxidopa, including the following: (1) it is directly converted to 1-norepinephrine by the action of the aromatic L-amino acid decarboxylase which is widely distributed in a living body, and thus has an effect of replenishing norepinephrine; (2) it has limited permeability through the blood-brain barrier into the brain; (3) it specifically recovers norepinephrine activated nerve functions which have decreased in the central and peripheral nervous system; and (4) it shows various actions, as norepinephrine, via the adrenaline receptors in various tissues.
Fibromyalgia—also referred to as fibromyalgia syndrome (FMS)—is a chronic pain illness or condition characterized by a generalized heightened perception of sensory stimuli and manifested by widespread aches, pain, and stiffness in muscles, fascia, and joints, as well as soft tissue tenderness. The most common sites of pain include the neck, back, shoulders, pelvic girdle, and hands, but any body part can be affected. Patients with fibromyalgia display abnormalities in pain perception in the form of both allodynia (pain with innocuous stimulation) and hyperalgesia (increased sensitivity to painful stimuli). Other symptoms typically include general fatigue, sleep disturbances, and depression.
Fibromyalgia is characterized by the presence of multiple tender points and a constellation of symptoms. The pain of fibromyalgia is profound, widespread, and chronic and is known to migrate to all parts of the body with varying intensity. Fibromyalgia pain has been described as deep muscular aching, throbbing, twitching, stabbing and shooting pain. Neurological complaints such as numbness, tingling, and burning are often present and add to the discomfort of the patient. Pain severity and stiffness is often worse in the morning, and aggravating factors include cold/humid weather, non-restorative sleep, physical and mental fatigue, excessive physical activity, physical inactivity, anxiety, and stress.
Fatigue associated with fibromyalgia can itself be debilitating, interfering with even the simplest daily activities. At times, fibromyalgia-associated fatigue can leave the patient with a limited ability to function both mentally and physically. Many fibromyalgia patients also have an associated sleep disorder that prevents deep, restful, restorative sleep. Studies have documented specific and distinctive abnormalities in the stage 4 deep sleep of fibromyalgia patients. During sleep, individuals with fibromyalgia are constantly interrupted by bursts of awake-like brain activity limiting the amount of time they spend in deep sleep. Additional symptoms associated with fibromyalgia can include the following: irritable bowel and bladder, headaches and migraines, restless legs syndrome (periodic limb movement disorder), impaired memory and concentration, skin sensitivities and rashes, dry eyes and mouth, anxiety, depression, ringing in the ears, dizziness, hypotension, vision problems, Raynaud's Syndrome, neurological symptoms, and impaired coordination, as well as other symptoms.
Currently there are no known diagnostic tests specific to fibromyalgia. Accordingly, diagnosis generally arises from evaluation of patient histories, self-reported symptoms, physical examination, and an accurate manual “tender point” examination based on the standardized criteria from the American College of Rheumatology (ACR). As defined by ACR guidelines, FMS involves the presence of pain for over three months duration in all four quadrants of the body, as well as along the spine. In addition, pain is elicited by palpation in at least 11 out of 18 “tender points”. It is estimated that it takes an average of five years for a fibromyalgia patient to get an accurate diagnosis, and many fibromyalgia symptoms overlap with those of other conditions. Moreover, the presence of comorbidities (such as rheumatoid arthritis or lupus) does not rule out a fibromyalgia diagnosis.
The etiology and pathophysiology of fibromyalgia are unknown; however, it is generally believed to include central nervous system involvement. Most researchers agree fibromyalgia is a disorder of central processing with neuroendocrine/neurotransmitter dysregulation. Fibromyalgia patients often experience pain amplification due to abnormal sensory processing in the central nervous system. Furthermore, studies show multiple physiological abnormalities in fibromyalgia patients, including: increased levels of substance P in the spinal cord; low levels of blood flow to the thalamus region of the brain; HPA axis hypofunction; low levels of serotonin and tryptophan; and abnormalities in cytokine function. Recent studies indicate the possibility of a genetic susceptibility to fibromyalgia.
Treatment of fibromyalgia is often multi-faceted and typically seeks to alleviate the associated symptoms rather than treat the condition itself. Medications, such as analgesics, anti-inflammatories, and muscle relaxants can be beneficial in reducing pain. Antidepressants may also be prescribed. Complementary therapies include: physical therapy, therapeutic massage, myofascial release therapy, water therapy, light aerobics, diet adjustments, acupressure, application of heat or cold, acupuncture, yoga, relaxation exercises, breathing techniques, aromatherapy, cognitive therapy, biofeedback, herbs, nutritional supplements, and osteopathic or chiropractic manipulation. One or more of these may be used.
Despite all of the above approaches for management of fibromyalgia, there remains an ongoing search for effective drug treatment of fibromyalgia. Multiple studies have been performed around a wide variety of compounds, and such studies are further referenced in U.S. Pat. No. 6,610,324, which is incorporated herein by reference. None of the previously evaluated drugs have shown particularly useful for long-term treatment of fibromyalgia beyond symptomatic alleviation, and the need for effective drug treatment of fibromyalgia persists.